Lung disease is the number three killer in America, responsible for one in seven deaths, and lung disease and other breathing problems are the number one killer of babies younger than one year old. Today, more than 30 million Americans are living with chronic inflammatory lung diseases such as emphysema and chronic bronchitis. In addition, approximately 150,000 Americans are affected by acute respiratory distress syndrome (ARDS) each year.
Many lung diseases are associated with lung inflammation. For example, ARDS involves the rapid onset of progressive malfunction of the lungs, and is usually associated with the malfunction of other organs due to the inability to take up oxygen. The condition is associated with extensive lung inflammation and small blood vessel injury in all affected organs. ARDS is commonly precipitated by trauma, sepsis (systemic infection), diffuse pneumonia, and shock. It also may be associated with extensive surgery, and certain blood abnormalities. In many cases of ARDS and other inflammatory lung diseases, the inflammatory response that accompanies the underlying disease state is much more dangerous than the underlying infection or trauma.
Many approaches to the prevention and management of ARDS have been unsuccessful or inconclusive. Treatments that have not improved outcome or prevented ARDS include monoclonal antibody to endotoxin, monoclonal antibody to tumor necrosis factor, interleukin-1 receptor antagonist, prophylactic (early) positive end-expiratory pressure (PEEP), extracorporeal membrane oxygenation and extracorporeal CO2 removal, IV albumin, volume expansion and cardiotonic drugs to increase systemic O2 delivery, corticosteroids in early ARDS, parenteral ibuprofen to inhibit cyclooxygenase, prostaglandin E1, and pentoxifylline.
Other common treatments for ARDS are also problematic. For example, there are safety and toxicity concerns regarding the use of inhaled NO. Inhaling very high levels of NO (5,000 to 20,000 ppm) can be lethal, causing a severe and acute accumulation of fluid in the lungs (pulmonary edema) and methomoglobinemia. Although OSHA has set the safety limit for NO2 at 5 ppm, some investigators have found that prolonged exposure to even 2 ppm of NO2 can be injurious to the lungs. Corticosteroids are of no proven benefit in acute ARDS, although anecdotal reports suggest benefit in some subjects with ARDS in the late fibroproliferative phase, which may develop after 7 to 10 days of mechanical ventilation. Mechanical ventilation, itself, carries risks, as well. For instance, tension pneumothorax is associated with the use of positive pressure ventilation (PPV) and PEEP, and may occur suddenly.
In view of the above, there exists a need for new therapies to treat inflammatory lung disease, particularly agents that suppress the inflammation associated with pneumonia, ARDS, respiratory distress of prematurity, chronic bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, and pulmonary sarcoidosis.